The present invention relates to new esters derived from substituted phenyl-cyclohexyl compounds, which are derived from Tramadol. The obtained compounds have a higher analgesic activity, a lower toxicity and a longer effective time period than Tramadol.
The treatment of pain is of great importance in the field of medicine. The pharmacological agents presently used for the treatment of pain can be primarily classified into two large groups: opioid compounds and non-steroidal anti-inflammatories (NSAIs). The NSAIs are only useful in the case of light or moderate pain; severe pain has traditionally been treated with opiod compounds. However, these opioid compounds have several undesirable side effects, such as constipation, respiratory depression, tolerance and possibility of addiction.
U.S. Pat. No. 3,652,589 describes a type of analgesic compounds with a structure of substituted cycloalkanol phenol ethers having a basic amino group in the cycloalkyl ring. Among them the (1R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol compound, generally known as Tramadol, is specially noted and specifically claimed in said patent. 
A series of products derived from the above, in which the dehydration in the cycloalkanol ring has occurred together with the demethylation of the methoxyl in the 3 position of the phenyl ring, of structure: 
have been described in the Dutch patent NL 6610022.
This patent also describes products derived from those of said US patent, in which the methoxyl group in the 3 position of the phenyl ring has been demethylated. That is, products of structure: 
O-demethyltramadol is included among those products described in patent NL 6610022, said product having been described as one of the metabolization products of Tramadol (Von W. Lintz et al. Arzneim-Forsch (Drug Res) 31 (II); 1932-43 (1982). The analgesic activity of Tramadol is attributed to its (+) isomer (Lars Poulsen et al. Clin. Pharmacol. Ther (St. Louis) 1996, 60 (6), 636-644). However, there is no data as to the clinical use of the O-demethyltramadol metabolite.
More recently, in patent EP 753506, new derivatives of Tramadol have been described, which are O-demethylsubstituted, halogenated at position 1 and/or 3-cyclohexyl substituted.
Tramadol has an opioid agonist effect. However, the clinical experience with Tramadol shows that in spite of this, it does not present some of the side effects typical of the opioid agonists, such as respiratory depression (W. Vogel et al. Arzneim. Forsch (Drug Res) 28 (I), 183 (1978)), constipation (I. Arend et al. Arzneim. Forsch (Drug Res) 28 (I), 199 (1978), tolerance (L. Flohe et al., Arzneim. Forsch (Drug Res) 28 (I), 213 (1978)) and possibility of abuse (T. Yenagita et al., Arzneim. Forsch (Drug Res) 28 (I), 158 (1978)). Some side effects specific for Tramadol have been found, which are caused when it is injected intravenously (i.v.) and quickly, such as hot flushes and sweating.
Another of the disadvantages associated with Tramadol is its short effective time period (T. Matthiesen, T. Wohrmann, T. P. Coogan, H. Uragg, xe2x80x9cThe experimental toxicology of tramadol: an overviewxe2x80x9d, Toxicology Letters 95, 63-71, (1998)).
U.S. Pat. No. 5,733,936 (hereinafter, xe2x80x9cthe ""936 patent) discloses some esters of 6-dimethylaminomethyl-1-phenyl-cyclohexane in the general formula of the description section with analgesic activity and low toxicity.
The object of the ""936 patent is to obtain esters, phosphates, ethers, phenols, carbonates, carbamates, etc of derivatives of 6-dimethylaminomethyl-1phenyl-cyclohexane, said derivatives can be substituted in the 5-position of ciclohexyl (according to the meaning of R2 and R3 of the claims) as well as of tehir dehydroxilated, chlorinated, phluorated analog compounds.
Moreover, although the ""936 patent discloses some esters of 6-dimethylaminomethyl-1-phenyl-cyclohexane, none of the examples in the ""936 patent refer to the ester of O-demethyltramadol. None of these examples includes compounds which have the tertiary OH characteristic of O-demethyltramadol. In particular, Example 13 which is the closest to the application discloses an ester of an analog of O-demethyltramadol with acetyl salicylic acid and not an ester of O-demethyltramadol. Therefore, the ""936 patent does not disclose an ester of O-demethyltramadol with the characteristic hydroxyl group in the 1-position. The ""936 patent discloses no working examples of an ester of O-demethyltramadol. The three other esters examplified (Examples 14, 15, 16) also lack the tertiary hydroxyl group.
Therefore, stability, activity and side effects data could not have been foreseen nor suggested. According to the present application a surprising effect is achieved with the compounds of formula I.
Based on the above background of the invention, the compounds with an analgesic activity similar to or higher than that of Tramadol and with a lower toxicity and with a higher effective time period are still of interest.
The present invention relates to new esters of O-demethyltramadol or its 1,2-dehydrated derivative.
The analgesic activity of these compounds has been found to be higher than that of Tramadol with a lower toxicity and a longer effective time period when administered orally (see FIG. 1).
In particular, the present invention describes and claims those products of general formula (I), its salts and optical isomers, as well as the process for obtaining them.
The products of the present invention are represented by the following general formula (I): 
Shows possibility of asynumetric carbons
where R1 is: 
R2 is: OH;
R3 is: H;
or R2 and R3 together form a double bond;
R4 is: H or C1-C2 alkyl;
R5 is: H, NH2, NHxe2x80x94R11 or Oxe2x80x94R11;
R6 is: H, COxe2x80x94R11, Oxe2x80x94R11 or halogen;
R7 is: H, C1-C5 alkyl, C2-C5 O-alkenyl, phenyl, or R6 and R7 are xe2x80x94Chxe2x95x90CR12-CR13xe2x95x90CHxe2x80x94, forming an optionally substituted condensed aromatic ring;
R8 is: OH, xe2x80x94Oxe2x80x94COxe2x80x94N (CH3)2 or NHxe2x80x94R11;
R9 and R10 are: H or C1-C4 alkyl, whether equal ordifferent, or form a xe2x80x94CH2xe2x80x94CH2xe2x80x94 group;
R11 is: phenyl; phenyl optionally substituted by 1 or more of the following substituents: halogen (Cl, Br, I), NO2, C1-C6 alkyl, C2-C6 alkenyl, OH, or NH2;
R12 and R13 are: H, or C1-C3 O-alkyl, whether equal or different.
When R1 is A, preferably, R4 is methyl or H, R5 is NH2, 2,5-dichlorophenylamino or H, R6 is substituted CO-phenyl or H, R7 is isobutyl or H, or R6 and R7 form a substituted condensed aromatic ring.
More preferably, when R1 is A, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-(4-isobutyl-phenyl)-propionate
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate
When R1 is B, preferably, R8 is OH or xe2x80x94Oxe2x80x94COxe2x80x94N(CH3)2.
More preferably, when R1 is B, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-hydroxybenzoate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-hydroxybenzoate
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-dimethylcarbamoyloxy-benzoate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-dimethylcarbamoyloxy-benzoate.
When R1 is C, preferably, R9 is methyl or H or forms a xe2x80x94CH2xe2x80x94CH2xe2x80x94 group with R10. More preferably, when R1is C, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.
The compounds of general formula (I) of the present invention can be obtained by a general process which is characterised by reacting a compound of general formula (II) with the corresponding acid or acid derivative of general formula III. 
Where R1, R2, R3 have the above defined meaning, and L=OH, halogen, 
Oxe2x80x94R14 or xe2x80x94COxe2x80x94 R15,
being
R14=C1-6 alkyl, phenyl, optionally substituted phenyl, and
R15=alkyl, a phenyl ring optionally substituted by one or more substituents or a heterocyclic ring optionally substituted by one or more substituents.
Preferably L is OH or Halogen.
The reaction is carried out in an inert solvent, preferably dichloromethane, tetrahydrofuran, etc., in a temperature range of xe2x88x9220xc2x0 to 120xc2x0 C., preferably a range of 0xc2x0 to 35xc2x0 C., and preferably in the presence of a condensation promoting agent, such as carbonyldiimidazol, dicyclohexylcarbo-diimida, etc.
The compounds of formula (II) are obtained according to the methods disclosed in the literature (NL 6610022 or Flick et al. Arzneim. Forsch/Drug Res. (1978), 28 (I), 107-113).
Analgesic Activity Tests
The pharmacological activity of the products of the present invention was tested in vivo in several experimental models, which are known to evaluate the pain in animals.
a) Hot Plate Method
The method that was used is described by Eddy N. B. and Leimbach D. (J. Pharm. Exp. Ther. 107: 385-393, 1953). The analgesic effect of the products was evaluated analysing the behaviour of the animals on a hot surface at 55xc2x0 C.xc2x11xc2x0 C.
Male Swiss mice weighing 20-25 g were used. The compounds being tested were administered orally or intraperitoneally 1 hour o 30 minutes before starting the test, respectively.
The process consisted of placing the animals on the plate and keeping them in a Plexiglas cylinder 25 cm high and 21 cm high. The time the animals took to jump off the hot surface was determined. The animals were selected before starting the test so that those that took longer than 10 seconds to jump off were not included in the group that would receive treatment.
30 minutes after administering the product being tested, the test was repeated and the maximum time it took the animals to jump off was again recorded. Those animals that did not jump off after 60 seconds were removed from the plate to avoid any injuries and were recorded as 100% protection.
The results are expressed as the C of jump time increase calculated as follows:       %    ⁢          xe2x80x83        ⁢    jump    ⁢          xe2x80x83        ⁢    time    ⁢          xe2x80x83        ⁢    increase    =                    (                              treated            ⁢                          xe2x80x83                        ⁢            jump            ⁢                          xe2x80x83                        ⁢            time                    -                      base            ⁢                          xe2x80x83                        ⁢            jump            ⁢                          xe2x80x83                        ⁢            time                          )                    base        ⁢                  xe2x80x83                ⁢        jump        ⁢                  xe2x80x83                ⁢        tieme              xc3x97    100  
In order to determine the duration of the analgesic effect of the orally administered products, the analgesic activity was evaluated on the hot plate 1, 3, 6, 8, and 24 hours after the administration of the product, as well as the control group which received treatment only with the vehicle. The base responses were evaluated at 30 and 5 minutes prior to administering the products.
b) Determination of the DL50 in the Products.
(EUDRA/S/87/011, Single Dose Toxicity, European Directive 75/318/EEC) (ICH S4, Toxicity Studies, single dose and repeated dose, CPMP vol III Feb. 87, Single dose toxicity)
Male Swiss mice of the same batch weighing 20-25 g are used in order to estimate the acute toxicity of the products.
Prior to administering the products, the animals were forced to fast for 12 hours with no intake of food but free access to water. Several subgroups of 10 animals were randomly selected and orally given increasing doses of the products in single administration, after which they remained under observation for a period of 14 days with free access to water and food. Finally, the number of dead animals of each subgroup was quantified and the value of the DL50 was calculated (1-2).